Heat shock protein 90 inhibitors overcome chemoradiotherapy resistance conferred by erbB2 and NFκB overexpression in muscle-invasive bladder cancer
| Project/Area Number |
19791103
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Urology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
YOSHIDA Sochiro Tokyo Medical and Dental University, 医学部・附属病院, 医員 (80383280)
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| Project Period (FY) |
2007 – 2009
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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥3,810,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥510,000)
Fiscal Year 2009: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | 浸潤性膀胱癌 / 化学放射線療法 / anti-apoptotic protein |
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| Research Abstract |
Improvement of response of bladder cancer to chemoradiotherapy is expected not only to provide the patients a chance of bladder preservation but to improve their survival outcomes. We identified key molecules responsible for chemoradiotherapy resistance in clinical cohort. In the patients with muscle bladder cancer underwent radiotherapy plus concomitant cisplatin at low-dose (low-dose chemoradiotherapy, LCRT) as an induction therapy prior to curative surgery, overexpression of erbB2 and nuclear NFκB p65 in transurethral biopsy specimens obtained prior to LCRT significantly and independently associates with LCRT resistance. Destabilizing erbB2 and inhibiting nuclear translocation of NFκB by using Heat shock protein 90 (Hsp90) inhibitor; 17-DMAG, sensitizes bladder cancer cell lines (T24, UM-UC-3 and 5637) to in vitro LCRT by enhancing apoptosis. This sensitizing effect was not observed in primarily cultured normal human urothelial (NHU) cells. Pretreatment with Hsp90 inhibitor; 17-AAG, successfully overcame in vivo LCRT resistance of human bladder cancer xenograft of UM-UC-3 bladder cancer cells overexpressing erbB2 and NFκB. Hsp90 inhibitors, simultaneously abrogating erbB2 and NFκB pathways, tumor-selectively sensitize bladder cancer cells to LCRT and overcome LCRT resistance in preclinical models.These results encourage clinical trials of Hsp90 inhibitors adjunct to chemoradiotherapy to improve oncological outcomes and QOL in patients with muscle bladder cancer.
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Report
(4 results)
Research Products
(15 results)
